Pyrazole derivatives

ABSTRACT

The present invention relates to nitro-vinyl-pyrazole compounds of formula (B)wherein ring A, RB2 and RB3 are as defined in claim 1, as well as the manufacture of such compounds and their subsequent use in the production of agrochemicals and/or pharmaceuticals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/782,866, filed Feb. 5, 2020, which claims priority to PatentApplication No. GB1901559.3 filed in the United Kingdom on Feb. 5, 2019,the entire contents of each which are incorporated herein by reference.

The present invention relates to pyrazole derivatives of formula (B) andformula (C) as described herein, which are valuable intermediates in theproduction of agrochemicals and pharmaceuticals. The invention extendsto the manufacture of such pyrazole derivatives, and their subsequentuse in the manufacture of agrochemicals and/or pharmaceuticals.

In a first aspect there is provided a compound of formula (B)

wherein ring A as is a di-substituted pyrazole, substituted a ringnitrogen by R^(B2) and substituted on a ring carbon by R^(B3), whereinR^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl and R^(B3) is halogen,C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl,C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, or C₁-C₃alkyl.

In a second aspect there is provided a compound of formula (C)

wherein ring A as is a di-substituted pyrazole, substituted on a ringnitrogen by R^(B2) and substituted on a ring carbon by R^(B3), whereinR^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) is halogen,C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl,C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, or C₁-C₃alkyl.

Compounds of formulae (B) and (C), may be used as intermediates in themanufacture of pharmaceuticals and agrochemicals comprisingpyrazolo-pyrrolidone motifs. For example, US2007/0123508 describes2-oxo-1-pyrrolidone derivatives for use as PAR2 inhibitors, compounds offormulae (B), (C), (D) and (E) may be used in the synthesis of suchcompounds wherein R¹ of the compound of US2007/0123508 is a substitutedpyrazole. The manufacture of novel herbicidal compounds using compoundsof formula formulae (B), and (C), is also described herein.

Compounds of formula (B) may be prepared from a halogenated pyrazole offormula (A)

wherein ring A, R^(B2) and R^(B3) are as defined above, and Hal ishalogen selected from iodo, bromo and chloro, by reacting the compoundof formula (A) with isopropylmagnesium chloride-lithium chloride in asuitable solvent, such as tetrahydrofuran, at −20° C. After two hours,1-dimethylamino-2-nitroethylene is added and the reaction is slowlywarmed to room temperature over the course of one hour. This affords thedesired nitrovinyl pyrazole of formula (B) after work up andpurification (Reaction scheme 1). Compounds of formula (A) are eitherknown or can be prepared according to methods well known in the art.

Nitrovinyl pyrazole compounds of formula (B) can also be prepared byreacting the corresponding pyrazole aldehyde (x) and nitromethanetogether, with a suitable base, in a suitable solvent followed bydehydration step, as shown in Reaction scheme 1.1 below. Such methodsare reported in WO2016/100050 and WO2019/169153.

The nitrovinyl pyrazole compound of formula (B) is then reacted with amalonate, such as diethylmalonate, in a suitable solvent, such astoluene, under enantioselective nickel catalysis as described in J. Am.Chem. Soc. 2005, 127, 9958-9959, to afford the enantio-enriched malonateaddition product that is the compound of formula (C) as shown inReaction scheme 2.

In compounds of formulae (A), (B), and (C), as described herein, ring Ais a pyrazole moiety carrying two substituents, wherein one of saidsubstituents (R^(B2)) is borne by a ring nitrogen, and a secondsubstituent (R^(B3)) is borne on a ring carbon atom. Clearly with such aconfiguration, A is carbon linked to the rest of the respectivemolecule.

When A is di-substituted and R^(B3) is borne on the ring carbon atomadjacent the substituted ring nitrogen atom said R^(B3) substituent maybe defined as R^(B3SN). For the avoidance of doubt R^(B3SN) is asub-definition of R^(B3) used purely to denote positional placementwithin the pyrazole moiety, and therefore R^(B3SN) is also selected fromthe group consisting of halogen, C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy,C₁-C₃alkoxy, and C₁-C₃alkyl. Thus, when A is di-substituted, it may berepresented by groups A¹, A², A³, A⁴, or A⁵, as shown below, whereinR^(B2), R^(B3) and R^(B3SN) are as defined above and the jagged linedenotes the point of attachment to the rest of the relevant molecule.

Groups A¹ and A² are particularly preferred, with A² being the mostpreferred of the di-substituted pyrazoles.

Preferably R^(B2) is selected from the group consisting of methyl,ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl and trifluoroethyl. More preferably R^(B2) is selectedfrom the group consisting of methyl, ethyl, n-propyl, trifluoromethyland difluoroethyl. More preferably still, R^(B2) is selected from thegroup consisting of methyl, ethyl, and difluoroethyl.

Preferably R^(B3) (and thus also R^(B3SN)) is selected from chloro,fluoro, bromo, methyl, ethyl, diluoromethyl, trifluoromethylC₁-C₃haloalkoxy, C₁-C₃alkoxy, or C₁-C₃alkyl.

As used herein, the term “halogen” or “halo” refers to fluorine(fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo),preferably fluorine, chlorine or bromine.

Each alkyl moiety either alone or as part of a larger group may bestraight-chained or branched, and as used herein the term specificallyalso includes cyclopropyl. Typically, the alkyl is, for example, methyl,ethyl, n-propyl, cylcopropyl, and isopropyl.

Table 1 and 2 below provide specific examples of compounds of formulae(B) and (C) for use in the invention.

TABLE 1 Compounds of formula B according to the invention Cmpd. No. NameStructure B.001(E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethenamine

B.002 (E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]ethenamine

B.003 (E)-2-(5-chloro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy- ethenamine

B.004 (E)-2-(5-chloro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy- ethenamine

B.005 (E)-2-(5-fluoro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy- ethenamine

B.006 (E)-2-(5-fluoro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy- ethenamine

TABLE 2 Compounds of formula C according to the invention Cmpd. No. NameStructure C.001 diethyl 2-[(1R)-2-(dihydroxyamino)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethyl]propanedioate

C.002 diethyl 2-[(1S)-2-(dihydroxyamino)-1-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]ethyl]propanedioate

C.003 diethyl 2-[(1R)-1-(5-chloro-1-methyl-pyrazol-3-yl)-2-(dihydroxyamino)ethyl]propanedioate

C.004 diethyl 2-[(1S)-1-(5-chloro-1-methyl-pyrazol-4-yl)-2-(dihydroxyamino)ethyl]propanedioate

C.005 diethyl 2-[(1R)-2-(dihydroxyamino)-1-(5-fluoro-1-methyl-pyrazol-3-yl)ethyl]propanedioate

C.006 diethyl 2-[(1S)-2-(dihydroxyamino)-1-(5-fluoro-1-methyl-pyrazol-4-yl)ethyl]propanedioate

Compounds of formula (B) and (C) as described herein, may be used tosynthesise pyrazolo-lactam-carboxylates of formula (D),

wherein ring A, R^(B2) and R^(B3) are as defined herein, andpyrazolo-lactam-carboxylic acid derivatives of formula (E),

also wherein ring A, R^(B2) and R^(B3) are as defined herein. Thesenovel compounds form yet further aspects of the invention.

The reductive cyclisation of the compound of formula (C), using asuitable reducing agent, such as sodium borohydride, with a suitablecatalyst, such as nickel chloride, in a suitable solvent, such asethanol, affords a pyrazolo-lactam-carboxylate of formula (D) (Reactionscheme 3 below).

The compound of formula (D) may then be hydrolysed in an aqueoushydroxide/ethanol mixture to afford the appropriatepyrazolo-lactam-3-carboxylic acid derivative of formula (E), as shown inReaction scheme 4.

Compounds of formula (D) and formula (E) are also valuable intermediatesin the production of pyrazolo-lactam herbicides, in particular as theygive rise to the preferred herbicidal enantiomer. Tables 3 and 4 belowprovide specific examples of compounds of formulae (D) and (E) for usein the invention.

TABLE 3 Compounds of formula (D) according to the invention Cmpd. No.Name Structure D.001 ethyl(3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate

D.002 ethyl (3R,4S)-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxylate

D.003 ethyl (3R,4R)-4-(5-chloro-1-methyl-pyrazol-3-yl)-2-oxo-pyrrolidine-3-carboxylate

D.004 ethyl (3R,4S)-4-(5-chloro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine-3-carboxylate

D.005 ethyl (3R)-4-(5-fluoro-1-methyl-pyrazol-3-yl)-2-oxo-pyrrolidine-3-carboxylate

D.006 ethyl (3R)-4-(5-fluoro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine-3-carboxylate

TABLE 4 Compounds of formula (E) according to the invention Cmpd. No.Name Structure E.001(3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid

E.002 (3R,4S)-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxylic acid

E.003 (3R,4S)-4-(5-chloro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine-3-carboxylic acid

E.004 (3R,4S)-4-(5-chloro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine-3-carboxylic acid

E.005 (3R,4R)-4-(5-fluoro-1-methyl-pyrazol-3-yl)-2-oxo-pyrrolidine-3-carboxylic acid

E.006 (3R,4S)-4-(5-fluoro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine-3-carboxylic acid

The process for the manufacture of novel pyrazolo-lactam herbicides offormula (G) from compounds of formula (E), is described below in generalterms in Reaction schemes 5 and 6, and with respect to a specificherbicidal compounds in the Examples.

Compounds of formula (E) are methylated on the lactam nitrogen usingexcess base, such as potassium tertiary butoxide, with methyl iodide oralternative methylating reagents, in a suitable solvent, such astetrahydrofuran (Reaction scheme 5 above).

The 3-carboxyl substituted N-methyl lactam of formula (F) is coupledwith an aniline of formula R²—NH₂ (wherein R² is as defined infra) toafford a herbicidal pyrazolo-lactam carboxamide of formula (G), usingstandard amide coupling conditions, such as propanephosphonic acidanhydride in a suitable solvent, such as dichloromethane, with asuitable base (Reaction scheme 6).

For anilines of formula R²—NH₂ and herbicidal compounds of formula (G),R² substituents include hydrogen, C₁-C₆alkyl, —C_(r)alkoxyC_(s)alkyl,C₁-C₆haloalkyl, —C_(r)alkoxyC_(s)haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,and —(CR²¹R²²)_(t)R²⁰, wherein each R²⁰ is independently —C(O)OR²³,—OC(O)R²³, —C₃-C₆cycloalkyl, or an -aryl, -aryloxy, -heteroaryl,-heteroaryloxy or -heterocyclyl ring, wherein said ring is optionallysubstituted by 1 to 3 independent R²⁵; r is an integer of 1, 2, 3, 4, or5, s is an integer of 1, 2, 3, 4, or 5, and the sum of r+s is less thanor equal to 6; t is an integer of 0, 1, 2, 3, 4, 5 or 6, each R²¹ isindependently hydrogen or C₁-C₂ alkyl; each R²² is independentlyhydrogen or C₁-C₂ alkyl; R²³ is hydrogen or C₁-C₄alkyl.

In certain embodiments, where R² is an aryl or heteroaryl ringoptionally substituted by 1 to 3 R²⁵, and said aryl or heteroaryl ringis selected from the group consisting of a phenyl, pyridinyl, and athienyl ring system, it may be represented by the following genericstructure

wherein ring B is a phenyl, pyridinyl, or thienyl ring, p is an integeror 0, 1, 2, or 3, and the jagged line represents the point of attachmentof the ring to the rest of the molecule, in this case via the amidenitrogen.

In certain embodiments R² is selected from the group consisting of R²-1,R²-2, R²-3, R²-4, R²-5, and R²-6, wherein p and the jagged line are asdescribed previously, and each R²⁵ is independently halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, cyano, nitro,C₁-C₆alkylthio, C₁-C₆alkylsulphinyl, or C₁-C₆alkylsulphonyl

More preferably each R²⁵ is independently halogen, C₁-C₄ alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, or C₁-C₃haloalkoxy; even more preferably chloro,fluoro, bromo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, or C₁-C₂alkoxy; morepreferably still fluoro, ethyl, trifluoromethyl, difluoroethyl, methoxy,difluoromethoxy, or trifluoromethoxy. As stated herein, the value of pis 1, 2 or 3. Preferably p is 0, 1, or 2 and each R²⁵ is borne by a ringcarbon atom.

Anilines of formula R²—NH₂ are either known or can be prepared accordingto methods well known in the art.

Reaction schemes 1a, 2a, 3a, 4a, and 5a shown below exemplify thecompounds and processes of the invention as described above for apreferred set of embodiments, wherein the pyrazole ring in the compoundof formula (A) has the structure described as A2 supra. Unless otherwisestated, R^(B2), R^(B3), Hal, and ^(R2) are as defined hereinbefore.

Various aspects and embodiments of the present invention will now beillustrated in more detail by way of example. It will be appreciatedthat modification of detail may be made without departing from the scopeof the invention.

For the avoidance of doubt, where a literary reference, patentapplication, or patent, is cited within the text of this application,the entire text of said citation is herein incorporated by reference.

EXAMPLES Example 1: Preparation of the herbicidal compound(3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

The Nickel catalyst used in step 3, which catalyses the asymmetricmalonate addition to the nitro olefin, can be prepared as in J. Am.Chem. Soc. 2005, 127, 9958-9959.

Step 1 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole

The compound 1-methyl-5-(trifluoromethyl)pyrazol-3-amine (5.00 g, 30.3mmol) was stirred in 9M sulfuric acid (818 mmol, 91 mL) in a 500 mLbeaker, using an overhead stirrer at 0° C. (ice bath) until a homogenousmixture resulted. Sodium nitrite (60.6 mmol, 4.18 g), in 10 mL of water,was then added dropwise over 5 minutes, resulting in a colourlesssolution and the reaction was stirred at 0° C. for a further 20 minutes.Potassium iodide (75.7 mmol, 12.6 g), in 20 mL of water, was addeddropwise to the reaction and the mixture was then stirred for a further4 hours. The reaction was quenched with saturated sodium thiosulfateuntil the mixture became clear. The mixture was then diluted withdichloromethane and the phases were separated. The aqueous was furtherextracted with dichloromethane and the combined organic extracts werewashed with water, dried (MgSO4), filtered and concentrated under vacuumto afford a pale yellow oil. The crude product was purified by columnchromatography (EtOAc/hexanes gradient elution) to afford3-iodo-1-methyl-5-(trifluoromethyl)pyrazole as a colourless oil, 3.9 g,(47%). ¹H NMR (400 MHz, CDCl₃) δ=6.76 (s, 1H) 4.01 (d, J=0.61 Hz, 3H).

Step 2 1-Methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole

Isopropylmagnesium chloride-Lithium chloride in THE (23.55 mmol, 1.3mol/L) was added dropwise to 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole(5.0 g, 18.12 mmol) in THE (90 mL) at −20° C. and the mixture wasstirred for 2 hours. 1-Dimethylamino-2-nitroethylene (27.17 mmol, 3.321g) was added and the reaction was slowly warmed to RT over 1 hour. Thereaction mixture was then carefully quenched with 2 M HCl, and extractedwith ethyl acetate. The organic extracts were washed with brine, dried(MgSO4), filtered, concentrated and purified by chromatography(EtOAc/cyclohexane gradient elution) to afford1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (74.6%) as ayellow oil, 2.99 g (74.6%).

¹H NMR (400 MHz, CDCl₃) δ=7.89 (d, J=13.7 Hz, 1H), 7.63 (d, J=13.7 Hz,1H), 6.88 (s, 1H), 4.05 (d, J=0.6 Hz, 3H).

Step 3 Diethyl2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate

To a solution of1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (0.650 g, 2.94mmol) in toluene (19.5 mL) was added diethyl malonate (0.676 mL, 4.41mmol) followed byNickel(II)Bis[(1R,2R)—N1,N2-bis(phenylmethyl)-1,2-cyclohexanediamine-N1,N2]dibromide(0.0588 mmol, 0.0472 g), and the mixture was stirred at ambienttemperature for 20 hours.

The reaction mixture was washed with water (2×10 mL) and the organicphase separated, concentrated and purified by chromatography(EtOAc/cyclohexane gradient elution) to afford diethyl2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioateas pale yellow oil, 1.07 g (95%).

¹H NMR (400 MHz, CDCl₃) δ=6.53 (s, 1H), 5.01 (dd, 1H), 4.88 (dd, J=4.3,13.9 Hz, 1H), 4.35 (ddd, J=4.4, 7.7, 9.0 Hz, 1H), 4.22 (q, 2H), 4.16 (q,J=7.1 Hz, 2H), 3.90 (s, 3H), 3.89 (d, 1H), 1.26 (t, 3H), 1.20 (t, J=7.2Hz, 3H).

Step 4 Ethyl(3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate

To a solution of diethyl2-[(1R)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate(1.07 g, 2.81 mmol) in ethanol (42.1 mL) cooled to 0-5° C. (ice bath)under nitrogen, was added dichloronickel hexahydrate (2.95 mmol, 0.700g). Sodium borohydride (8.42 mmol, 0.325 g) was then added portionwiseto the pale greenish-blue solution. After 30 minutes the cooling wasremoved and the reaction mixture allowed to warm to ambient temperature.After stirring for 5 hours, at ambient temperature, the reaction mixturewas cooled to 5-10° C., in an ice-water bath, and slowly quenched withammonium chloride solution, and the mixture stirred for a further 20minutes. The mixture was then diluted with EtOAc (20 mL), and filteredthrough a bed of celite, washing through with portions of water andEtOAc. The collected two-phase mixture was concentrated to remove thebulk of solvent and the residue transferred to a separating funnel,diluted with EtOAc (20 mL) and the organic phase separated. The aqueousphase was further extracted with EtOAc (2×25 mL) and all organicextracts combined, passed through a phase separation concentrated andpurified by chromatography (EtOAc/hexanes gradient elution) to afford apale yellow oil, 0.61 g (77%) which crystallised on standing.

1H NMR (400 MHz, CDCl₃) δ=6.91 (br s, 1H), 6.47 (s, 1H), 4.28 (q, J=7.2Hz, 2H), 4.14 (q, 1H), 3.94 (d, 3H), 3.80 (dt, J=1.0, 9.0 Hz, 1H), 3.63(d, J=9.3 Hz, 1H), 3.52 (dd, J=8.2, 9.5 Hz, 1H), 1.32 (t, J=7.2 Hz, 3H).

Step 5(3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylicacid

To a solution of ethyl(3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate(0.61 g, 2.0 mmol) in ethanol (6.0 mL) and water (2.0 mL) at 0° C. (icebath) was added 2M sodium hydroxide (3 mL, 6.0 mmol). The reactionmixture was stirred at 0° C. for 30 minutes and then diluted with water(15 mL) and extracted with EtOAc (25 mL). The organic extracts werewashed with water (10 mL), and the aqueous extracts combined andacidified to pH 2 with dilute HCl. The acidified aqueous extracts werethen re-extracted with EtOAc (3×20 mL) and these organic extracts wererun through a phase separation cartridge and concentrated affording apale yellow oil, 0.54 g (quantitative) which crystallised on standing.

¹H NMR (400 MHz, CDCl3) δ=6.59 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H),3.85-3.77 (m, 1H), 3.72 (d, J=10.0 Hz, 1H), 3.66-3.58 (m, 1H).

Step 6(3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylicacid

To a stirred solution of(3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylicacid (0.57 g, 2.1 mmol, 0.57 g) in tetrahydrofuran (16 mL), at roomtemperature, under a nitrogen atmosphere was added potassium tertiarybutoxide (1.0M in THF) (4.5 mL, 4.5 mmol) giving a pale yellow finesuspension. To this suspension was added iodomethane (0.19 mL, 3.1mmol), and stirring at room temp was continued for 20 h. The stirredreaction mixture was acidified to pH2 with dilute HCl and the mixturewas diluted with water (10 mL) and extracted with EtOAc (3×30 mL). Thecombined organic extracts were washed with brine (15 mL), dried overmagnesium sulfate, filtered and the filtrate concentrated giving atransparent amber gum, 0.63 g ((quantitative).

¹H NMR: (400 MHz, CDCl3) δ=6.68 (s, 1H), 3.97 (q, 1H), 3.94 (s, 3H),3.76-3.68 (m, 3H), 2.99 (s, 3H).

Step 7(3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

To a solution of(3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylicacid (0.61 g, 2.1 mmol) in dichloromethane (15 mL) was added2,3-difluoroaniline (0.21 mL, 2.1 mmol). Propylphosphonic anhydride (50mass %) in ethyl acetate (2.3 g, 3.6 mmol, 2.1 mL) was then added, andthe reaction mixture was then immersed in a room temp water bath.N,N-Diisopropylethylamine (1.1 mL, 6.3 mmol) was added drop-wise, andthe reaction was stirred at room temperature for 2.5 hour. The reactionmixture was quenched by the addition of water (15 mL) and transferred toa phase sep cartridge. The aqueous was further extracted with DCM (2×10mL) and the combined organic extracts were concentrated and purified bychromatography (EtOAc/hexanes gradient elution) to afford a pink oil.Trituration with iso-hexane afforded a pale pink solid 398 mg (47%).

1H NMR: (400 MHz, CDCl₃) δ=10.16 (br s, 1H), 8.08-8.01 (m, 1H), 7.02(ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 6.69 (s, 1H), 4.09 (q,1H), 3.94 (s, 3H), 3.78 (d, J=9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (s,3H).

Chiral HPLC analysis, by the methods stated above, confirmed anenantiomeric ratio of 97:3.

Example 2 Preparation of(3S,4S)—N-(2,3-Difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamide

The herbicidal compound(3S,4S)—N-(2,3-Difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamidewas made in a directly analogous manner to that described above for(3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamidein Example 1 above. NMR data for the single enantiomer is as follows:

1HNMR (CDCl3) δ=10.05 (br s, 1H), 8.04-7.97 (m, 1H), 7.46 (s, 1H), 7.01(ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 4.21 (q, J=8.8 Hz,1H), 4.00 (s, 3H), 3.75 (t, J=9.5 Hz, 1H), 3.64 (d, J=9.4 Hz, 1H), 3.27(dd, J=8.1, 9.9 Hz, 1H), 2.97 (s. 3H).

The invention claimed is:
 1. A method, comprising: reacting a compoundof formula (A):

wherein ring A is a di-substituted pyrazole, substituted on a ringnitrogen by R^(B2) and substituted on a ring carbon by R^(B3), whereinR^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl and R^(B3) is halogen,C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; and Hal isiodo, bromo or chloro, with 1-dimethylamino-2-nitroethylene to form acompound of formula (B):


2. The method of claim 1, wherein the reacting further comprisesisopropylmagnesium chloride-lithium chloride and a solvent.
 3. Themethod of claim 2, wherein the solvent is tetrahydrofuran.
 4. The methodof claim 3, wherein the reacting is at −20° C.
 5. The method of claim 2,wherein the reacting is warmed to room temperature after adding1-dimethylamino-2-nitroethylene.
 6. The method of claim 2, wherein thecompound of formula (B) is selected from the group consisting of:(E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethenamine;(E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]ethenamine;(E)-2-(5-chloro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine;(E)-2-(5-chloro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine;(E)-2-(5-fluoro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine; and(E)-2-(5-fluoro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine.
 7. Themethod of claim 1, wherein the compound of formula (B) ring A is A1, A2,A3, or A5,

where the jagged line denotes attachment to the nitrovinyl moiety,R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) and R^(B3SN) arehalogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; orring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety,R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) is fluoro, bromo,iodo, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; orring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety,R^(B2) is ethyl, n-propyl, cyclopropyl, isopropyl, or C₁-C₃fluoroalkyl,and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, orC₁-C₃alkyl.
 8. The method of claim 1, wherein the compound of formula(B) ring A is A1, A2, A3, A4 or A5,

wherein R^(B3SN) is an R^(B3) substituent located on a carbon atomimmediately adjacent the nitrogen atom substituted with R^(B2), and thejagged line denotes attachment to the nitrovinyl moiety.
 9. The methodof claim 8, wherein the compound of formula (B) ring A is A1, A2, A3, orA5.
 10. A method, comprising: reacting a compound of formula (A):

wherein ring A is a di-substituted pyrazole, substituted on a ringnitrogen by R^(B2) and substituted on a ring carbon by R^(B3), whereina) R^(B2) is ethyl, n-propyl, cyclopropyl, isopropyl, orC₁-C₃fluoroalkyl and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy,C₁-C₃haloalkyl, or C₁-C₃alkyl, or b) R^(B2) is C₁-C₃ alkyl orC₁-C₃fluoroalkyl and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy,C₁-C₃haloalkyl, ethyl, n-propyl, cyclopropyl, or isopropyl, withnitromethane to form a compound of formula (B):


11. The method of claim 10, wherein the reacting further comprises abase.
 12. The method of claim 11, wherein the reacting further comprisesa solvent.
 13. The method of claim 12, wherein the reacting furthercomprises dehydrating with a dehydrating agent.
 14. The method of claim10, wherein the compound of formula (B) is selected from the groupconsisting of:(E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethenamine;(E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]ethenamine;(E)-2-(5-chloro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine;(E)-2-(5-chloro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine;(E)-2-(5-fluoro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine; and(E)-2-(5-fluoro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine.
 15. Themethod of claim 10, wherein the compound of formula (B) ring A is A1,A2, A3, or A5,

where the jagged line denotes attachment to the nitrovinyl moiety, andwherein a) R^(B2) is ethyl, n-propyl, cyclopropyl, isopropyl, orC₁-C₃fluoroalkyl, and R^(B3) and R^(B3SN) are halogen, C₁-C₃haloalkoxy,C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl, or b) R^(B2) is C₁-C₃ alkylor C₁-C₃fluoroalkyl, and R^(B3) and R^(B3SN) are halogen,C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, ethyl, n-propyl,cyclopropyl, or isopropyl; or ring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety, andwherein a) R^(B2) is ethyl, n-propyl, cyclopropyl, isopropyl, orC₁-C₃fluoroalkyl, and R^(B3) is fluoro, bromo, iodo, C₁-C₃haloalkoxy,C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl, or b) R^(B2) is C₁-C₃ alkylor C₁-C₃fluoroalkyl, and R^(B3) is fluoro, bromo, iodo, C₁-C₃haloalkoxy,C₁-C₃alkoxy, C₁-C₃haloalkyl, ethyl, n-propyl, cyclopropyl, or isopropyl;or ring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety,R^(B2) is ethyl, n-propyl, cyclopropyl, isopropyl, or C₁-C₃fluoroalkyl,and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, orC₁-C₃alkyl.
 16. The method of claim 10, wherein the compound of formula(B) ring A is A1, A2, A3, A4 or A5,

wherein R^(B3SN) is an R^(B3) substituent located on a carbon atomimmediately adjacent the nitrogen atom substituted with R^(B2), and thejagged line denotes attachment to the nitrovinyl moiety.
 17. The methodof claim 16, wherein the compound of formula (B) ring A is A1, A2, A3,or A5.